Denis Lima Oliveira, Vinicius Francisco Cardoso, Jose Britto-Júnior, Vivian Fuguhara, Francesco Frecentese, Rosa Sparaco, Vincenzo Santagada, Giuseppe Caliendo, André Sampaio Pupo, Edson Antunes, Gilberto De Nucci
{"title":"在大鼠离体右心房中，(±)-普萘洛尔和(±)-4-NO2-普萘洛尔的负性促时效应是由于阻断了 6-硝基多巴胺受体。","authors":"Denis Lima Oliveira, Vinicius Francisco Cardoso, Jose Britto-Júnior, Vivian Fuguhara, Francesco Frecentese, Rosa Sparaco, Vincenzo Santagada, Giuseppe Caliendo, André Sampaio Pupo, Edson Antunes, Gilberto De Nucci","doi":"10.1007/s00210-024-03463-3","DOIUrl":null,"url":null,"abstract":"<p><p>The positive chronotropic action induced by 6-nitrodopamine (6-ND) is selectively blocked by β<sub>1</sub>-adrenoceptor antagonists at concentrations that do not affect the positive chronotropic effect induced by dopamine, noradrenaline, and adrenaline. Here, the effects of ( ±)-propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranolol were investigated in the rat isolated right atrium. The atrium was mounted in glass chambers containing gassed (95%O<sub>2</sub>:5%CO<sub>2</sub>) and warmed (37 °C) Krebs-Henseleit's solution, and the isometric tension registered (PowerLab system). ( ±)-Propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranolol caused concentration-dependent falls in the spontaneous atrial frequency (pIC<sub>50</sub>: 4.80 ± 0.10, 4.64 ± 0.10, and 4.95 ± 0.10, respectively). The calculated pA<sub>2</sub> values for ( ±)-propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranol on noradrenaline-induced positive chronotropism were 8.44 ± 0.08, 6.41 ± 0.07, and 9.21 ± 0.29, respectively. The positive chronotropism induced by 6-ND (10 pM) was blocked by ( ±)-propranolol (1 µM) and ( ±)-4-NO<sub>2</sub>-propranolol (30 nM), whereas ( ±)-7-NO<sub>2</sub>-propranolol (1 µM) had no effect on 6-ND-induced responses. The pIC<sub>50</sub> of ( ±)-propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranolol were significantly shifted to the right in L-NAME-treated atria. The discrepancy between pA<sub>2</sub> values of ( ±)-propranolol and its respective pIC<sub>50</sub> indicates that the falls in atrial rate induced by ( ±)-propranolol should not be attributed to b-adrenergic antagonism. The reduced chronotropism by ( ±)-propranolol was unaffected by the sodium channel inhibitors tetrodotoxin and lidocaine but that was abolished in atria pre-treated with ( ±)-4-NO<sub>2</sub>-propranolol. The finding that ( ±)-propranolol reduces spontaneous atrial rate only in concentrations that affect 6-ND-induced positive chronotropism confirms the role of this catecholamine as an endogenous modulator of heart chronotropism. ( ±)-4-NO<sub>2</sub>-Propranolol behaves as a selective antagonist of 6-ND in the rat isolated atrium.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"3965-3976"},"PeriodicalIF":3.1000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The negative chronotropic effects of (±)-propranolol and (±)-4-NO<sub>2</sub>-propranolol in the rat isolated right atrium are due to blockade of the 6-nitrodopamine receptor.\",\"authors\":\"Denis Lima Oliveira, Vinicius Francisco Cardoso, Jose Britto-Júnior, Vivian Fuguhara, Francesco Frecentese, Rosa Sparaco, Vincenzo Santagada, Giuseppe Caliendo, André Sampaio Pupo, Edson Antunes, Gilberto De Nucci\",\"doi\":\"10.1007/s00210-024-03463-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The positive chronotropic action induced by 6-nitrodopamine (6-ND) is selectively blocked by β<sub>1</sub>-adrenoceptor antagonists at concentrations that do not affect the positive chronotropic effect induced by dopamine, noradrenaline, and adrenaline. Here, the effects of ( ±)-propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranolol were investigated in the rat isolated right atrium. The atrium was mounted in glass chambers containing gassed (95%O<sub>2</sub>:5%CO<sub>2</sub>) and warmed (37 °C) Krebs-Henseleit's solution, and the isometric tension registered (PowerLab system). ( ±)-Propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranolol caused concentration-dependent falls in the spontaneous atrial frequency (pIC<sub>50</sub>: 4.80 ± 0.10, 4.64 ± 0.10, and 4.95 ± 0.10, respectively). The calculated pA<sub>2</sub> values for ( ±)-propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranol on noradrenaline-induced positive chronotropism were 8.44 ± 0.08, 6.41 ± 0.07, and 9.21 ± 0.29, respectively. The positive chronotropism induced by 6-ND (10 pM) was blocked by ( ±)-propranolol (1 µM) and ( ±)-4-NO<sub>2</sub>-propranolol (30 nM), whereas ( ±)-7-NO<sub>2</sub>-propranolol (1 µM) had no effect on 6-ND-induced responses. The pIC<sub>50</sub> of ( ±)-propranolol, ( ±)-4-NO<sub>2</sub>-propranolol, and ( ±)-7-NO<sub>2</sub>-propranolol were significantly shifted to the right in L-NAME-treated atria. The discrepancy between pA<sub>2</sub> values of ( ±)-propranolol and its respective pIC<sub>50</sub> indicates that the falls in atrial rate induced by ( ±)-propranolol should not be attributed to b-adrenergic antagonism. The reduced chronotropism by ( ±)-propranolol was unaffected by the sodium channel inhibitors tetrodotoxin and lidocaine but that was abolished in atria pre-treated with ( ±)-4-NO<sub>2</sub>-propranolol. The finding that ( ±)-propranolol reduces spontaneous atrial rate only in concentrations that affect 6-ND-induced positive chronotropism confirms the role of this catecholamine as an endogenous modulator of heart chronotropism. ( ±)-4-NO<sub>2</sub>-Propranolol behaves as a selective antagonist of 6-ND in the rat isolated atrium.</p>\",\"PeriodicalId\":18876,\"journal\":{\"name\":\"Naunyn-Schmiedeberg's archives of pharmacology\",\"volume\":\" \",\"pages\":\"3965-3976\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2025-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Naunyn-Schmiedeberg's archives of pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00210-024-03463-3\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Naunyn-Schmiedeberg's archives of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00210-024-03463-3","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/9 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
The negative chronotropic effects of (±)-propranolol and (±)-4-NO2-propranolol in the rat isolated right atrium are due to blockade of the 6-nitrodopamine receptor.
The positive chronotropic action induced by 6-nitrodopamine (6-ND) is selectively blocked by β1-adrenoceptor antagonists at concentrations that do not affect the positive chronotropic effect induced by dopamine, noradrenaline, and adrenaline. Here, the effects of ( ±)-propranolol, ( ±)-4-NO2-propranolol, and ( ±)-7-NO2-propranolol were investigated in the rat isolated right atrium. The atrium was mounted in glass chambers containing gassed (95%O2:5%CO2) and warmed (37 °C) Krebs-Henseleit's solution, and the isometric tension registered (PowerLab system). ( ±)-Propranolol, ( ±)-4-NO2-propranolol, and ( ±)-7-NO2-propranolol caused concentration-dependent falls in the spontaneous atrial frequency (pIC50: 4.80 ± 0.10, 4.64 ± 0.10, and 4.95 ± 0.10, respectively). The calculated pA2 values for ( ±)-propranolol, ( ±)-4-NO2-propranolol, and ( ±)-7-NO2-propranol on noradrenaline-induced positive chronotropism were 8.44 ± 0.08, 6.41 ± 0.07, and 9.21 ± 0.29, respectively. The positive chronotropism induced by 6-ND (10 pM) was blocked by ( ±)-propranolol (1 µM) and ( ±)-4-NO2-propranolol (30 nM), whereas ( ±)-7-NO2-propranolol (1 µM) had no effect on 6-ND-induced responses. The pIC50 of ( ±)-propranolol, ( ±)-4-NO2-propranolol, and ( ±)-7-NO2-propranolol were significantly shifted to the right in L-NAME-treated atria. The discrepancy between pA2 values of ( ±)-propranolol and its respective pIC50 indicates that the falls in atrial rate induced by ( ±)-propranolol should not be attributed to b-adrenergic antagonism. The reduced chronotropism by ( ±)-propranolol was unaffected by the sodium channel inhibitors tetrodotoxin and lidocaine but that was abolished in atria pre-treated with ( ±)-4-NO2-propranolol. The finding that ( ±)-propranolol reduces spontaneous atrial rate only in concentrations that affect 6-ND-induced positive chronotropism confirms the role of this catecholamine as an endogenous modulator of heart chronotropism. ( ±)-4-NO2-Propranolol behaves as a selective antagonist of 6-ND in the rat isolated atrium.
期刊介绍：
Naunyn-Schmiedeberg''s Archives of Pharmacology was founded in 1873 by B. Naunyn, O. Schmiedeberg and E. Klebs as Archiv für experimentelle Pathologie und Pharmakologie, is the offical journal of the German Society of Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie, DGPT) and the Sphingolipid Club. The journal publishes invited reviews, original articles, short communications and meeting reports and appears monthly. Naunyn-Schmiedeberg''s Archives of Pharmacology welcomes manuscripts for consideration of publication that report new and significant information on drug action and toxicity of chemical compounds. Thus, its scope covers all fields of experimental and clinical pharmacology as well as toxicology and includes studies in the fields of neuropharmacology and cardiovascular pharmacology as well as those describing drug actions at the cellular, biochemical and molecular levels. Moreover, submission of clinical trials with healthy volunteers or patients is encouraged. Short communications provide a means for rapid publication of significant findings of current interest that represent a conceptual advance in the field.
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